Abstract PR02: Epigenetic biomarkers in cell-free DNA for early detection of high-grade serous ovarian carcinoma

Abstract

Abstract Background: High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy, with a 5-year survival rate of 40% or less when diagnosed with late-stage disease. There is a dramatic benefit to early diagnosis of HGSOC with a 5-year survival rate of nearly 90% for stage I disease. Unfortunately, the majority of HGSOC is diagnosed as late-stage disease and there are no reliable early screening or diagnostic tests. The objective of this study is to identify tumor-specific aberrant DNA methylation alterations detectable in circulation in order to develop a biomarker to detect early-stage HGSOC. Methods: We performed reduced representation bisulfite sequencing (RRBS) on 33 stage 1 HGSOC tissues and 10 normal fallopian tube tissue samples from contralateral ovaries of patients with ovarian cancer. We selected the top 82 regions from RRBS for validation by targeted bisulfite amplicon sequencing in plasma. We successfully designed assays for 35 out of 82 regions. Targeted bisulfite amplicon sequencing was performed on these top 35 regions in a separate cohort of circulating tumor DNA extracted from 27 stage 1 HGSOC and 11 benign ovarian masses. We constructed a novel classifier model that we used to differentiate between patients with HGSOC and those with benign ovarian lesions. Results: We identified 10,972 statistically significant differentially methylated regions between stage 1 HGSOC and normal fallopian tube tissues using RRBS. We then applied the classifier model on the top 35 regions determined by targeted bisulfite amplicon sequencing data on an independent cohort of plasma samples. This demonstrated that 13 of the 35 regions were able to discriminate stage 1 HGSOC from benign tumors with a high sensitivity and specificity (Area Under Curve = 0.909). Conclusions: These novel, noninvasive biomarkers show promise as an early detection test for high-grade serous ovarian cancer. This abstract is also being presented as Poster A08. Citation Format: Ben Yi Tew, Gerald Gooden, David N. Buckley, Heather Miller, Monique Spillman, Lynda Roman, Bodour Salhia. Epigenetic biomarkers in cell-free DNA for early detection of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR02.